To live, aerobic organisms metabolize oxygen to generate energy. During this process, cells create reactive chemicals called reactive oxygen species (ROS). ROS can attack all cellular constituents, including lipids, proteins, and DNA. Such oxidative damage has been associated with the aging process and human disease, namely cancer and neurodegeneration. We have been interested in defining the biochemical and cellular mechanisms for repairing oxidative DNA damage. In particular, we have delineated the structure-function mechanisms and biological contributions of specific proteins that participate in the base excision repair (BER) pathway. This process involves the recognition and excision of DNA damage, and restoration of the normal genetic content. Defects in DNA repair can give rise to mutations or cell death, leading to the development of human disease. Much of our effort has involved defining the biochemical functions of Ape1, the major human protein that repairs abasic sites in DNA. This protein has been shown by us and others to contribute predominantly to the repair of abasic lesions, a frequent genetic damage. In addition, we have shown that Ape1 contributes to the repair of 3?-modifications in DNA, such as mismatches, phosphate groups, phosphogycolates, and tyrosyl residues. These findings expand the known repertoire of substrates processed by this enzyme, and suggest additional biological functions for Ape1. We have also recently discovered that the environmental metal, lead, is a potent inhibitor of Ape1 activity. These results suggest that this co-mutagenic heavy metal may elicit its carcinogenic effects by inhibiting the repair function of Ape1 in vivo. Studies are currently underway to address this issue. We have moreover initiated studies to determine the biochemical and cellular contributions of XRCC1, a major single-strand break repair factor. This protein functions primarily as a scaffolding component, orchestrating specific protein-protein interactions required for efficient DNA repair. We recently reported a novel link between XRCC1 and DNA replication, as XRCC1 was found to directly interact and co-localize with the replication factor PCNA. Other research emphases that continue are (i) delineating the functional impact of amino acid variation in the population and its role in disease susceptibility and (ii) devising mathematical models for assessing biological questions related to BER. Future studies will continue to build a basic, structure-function foundation for understanding matters associated with human health.